Substituted Pyrazoles As Ppar Agonists

Abstract

A compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof wherein: p is 0 or 1; q is 0 or 1; R 1 and R 2 are independently H or C 1-3 alkyl; R 3 and R 4 are independently H, C 1-6 alkyl, —OC 1-6 alkyl, halogen, OH, C 2-6 alkenyl or CF 3 ; R 5 is H, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one or more halogens, —COphenyl, —OC 1-6 alkyl, phenyl, morpholino, or C 2-6 alkenyl; R 6 is C 1-6 alkyl, halogen, —OCH 2 phenyl, morpholino, pyrrolidino, piperidino, thiophenyl, furanyl, pyridinyl, —OC 2-6 alkenyl, or phenyl, wherein said phenyl is optionally substituted by C 1-3 alkyl.

1 . A compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof  
     
       
         
         
             
             
         
       
       wherein:  
       p is 0 or 1;  
       q is 0 or 1;  
       R 1  and R 2  are independently H or C 1-3  alkyl;  
       R 3  and R 4  are independently H, C 1-6  alkyl, —OC 1-6  alkyl, halogen, OH, C 2-6  alkenyl or CF 3 ;  
       R 5  is H, or C 1-6  alkyl, wherein said C 1-6  alkyl is optionally substituted by one or more halogens, —C(O)phenyl, —OC 1-6  alkyl, phenyl, morpholino, or C 2-6  alkenyl;  
       R 6  is C 1-6  alkyl, halogen, —OCH 2  phenyl, morpholino, pyrrolidino, piperidino, thiophenyl, furanyl, pyridinyl, —OC 2-6  alkenyl, or phenyl, wherein said phenyl is optionally substituted by C 1-3  alkyl.  
     
   
   
       2 . A compound according to  claim 1  which is a selective hPPAR alpha/gamma agonist.  
   
   
       3 . A compound according to  claim 1  wherein p is 0.  
   
   
       4 . A compound according to  claim 1  wherein q is 0.  
   
   
       5 . A compound according to  claim 1  wherein p and q are 0.  
   
   
       6 . A compound according to  claim 1  wherein R 1  and R 2  are independently C 1-3  alkyl.  
   
   
       7 . A compound according to  claim 6  wherein R 1  and R 2  are both C 1-3  alkyl.  
   
   
       8 . A compound according to  claim 7  wherein R 1  and R 2  are both methyl.  
   
   
       9 . A compound according to  claim 1  wherein R 4  is H.  
   
   
       10 . A compound according to  claim 1  wherein R 3  is —C 1-3  alkyl or —OC 1-3  alkyl  
   
   
       11 . A compound according to  claim 10  wherein R 3  is methyl or —OCH 3 .  
   
   
       12 . A compound according to  claim 1  wherein R 3  is ortho to the depicted oxygen.  
   
   
       13 . A compound according to  claim 1  wherein R 3  is methyl.  
   
   
       14 . A compound according to  claim 1  wherein R 6  is C 1-6  alkyl.  
   
   
       15 . A compound according to  claim 1  wherein R 6  is in the para position to the depicted alkylene.  
   
   
       16 . A compound selected from: 
 2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[4-(1-methylethyl)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-{[4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-(2-propen-1-yl)phenyl]oxy}-2-methylpropanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-propylphenyl)oxy]-2-methylpropanoic acid;    2-{[4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-ethyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}-2-methylpropanoic acid;    2-{[4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-ethyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(2-methylpropyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[4-2-methylpropyl)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-{[4-{[({1-methyl-5-[4-(1-methylethyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}propanoic acid;    2-methyl-2-{[4-{[({1-methyl-3-[4-(1-methylethyl)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}propanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-(methylphenyl)oxy]-2-methylpropanoic acid;    2-{[4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}-2-methylpropanoic acid;    2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-ethyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-{[4-{[({1-methyl-5-[4-(2-methylpropyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-(methyloxy)phenyl]oxy}propanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-ethyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methyl propanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]-2-methylpropanoic acid;    2-[(4-[{]({5-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(1-methylethyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(4-morpholinyl)phenyl]-1H-pyrazol-3yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl4-{[({1-methyl-5-[4-(1-pyrrolidinyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(1-piperidinyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-({4-[({[5-(4-biphenylyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[3-(1-pyrrolidinyl)phenyl]-1H-pyrazol 5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-({4-[({[3-(4-biphenylyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-{4-[({[5-(4-tert-butylphenyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2,6-dimethylphenoxy}-2-methylpropanoic acid;    2-{4-[({[3-(4-tert-butylphenyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2,6-dimethylphenoxy}-2-methylpropanoic acid;    2-{2-chloro-4-[({[5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl}carbonyl}amino)methyl]-6-methylphenoxy}-2-methylpropanoic acid;    2-[4-({[(3-biphenyl-3-yl-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}methyl)-2-methylphenoxy]-2-methylpropanoic acid;    2-({4-[({[5-(4-butylphenyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-({4-[({[5-(4-bromophenyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-methyl-2-{2-methyl4-[({[1-methyl-5-(2′-methylbiphenyl-4-yl)-1H-pyrazol-3-yl]carbonyl}amino)methyl]phenoxy}propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(2-thienyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-[(4-{[({5-[4-(3-furanyl)phenyl]-1-methyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(4-pyridinyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-[(4-{[({5-[4-(2-furanyl)phenyl]-1-methyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-phenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-(2-methyl-4-[({[1-methyl-3-(2′-methylbiphenyl-4-yl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenoxy}propanoic acid;    2-{4-[({[5-(4-butylphenyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2,6-dimethylphenoxy}-2-methylpropanoic acid;    2-{[4-({2-{4-[({[5-(4-butylphenyl)-1-methyl-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-chloro-6-methylphenoxy}-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[4-(4-morpholinyl)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[3-(1-piperidinyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[3-(1-pyrrolidinyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-{2-methyl-4-[({[1-methyl-3-(3-piperidin-1-ylphenyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenoxy}propanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-5-yl}acetyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-3-yl}acetyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[4-(1-piperidinyl)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-{[4-({[(3-{[4-(11,-dimethylethyl)phenyl]methyl}-1-methyl-1H-pyrazol-5-yl)carbonyl]amino}methyl)-2-methylphenyl]oxy}-2-methylpropanoic acid;    2-({4-[({[3-[4-(1,1-dimethylethyl)phenyl]-1-(2-propen-1-yl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-[2-(methyloxy)ethyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-({4-[({[3-[4-(1,1-dimethylethyl)phenyl]-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-({4-[({[5-[4-(1,1-dimethylethyl)phenyl]-1-(phenylmethyl)-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-({5-[({[3-[4-(1,1-dimethylethyl)phenyl]-1-(2-phenylethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid;    2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-[2-(methyloxy)ethyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methyl propanoic acid hydrochloride;    2-[(4-{[({3-[4-(1,1-dimethylethyl)phenyl]-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-3-[4-(2-propen-1-yloxy)phenyl]-1H-pyrazol-5-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-methyl-2-{[2-methyl-4-({[(1-methyl-3-{4-[(phenylmethyl)oxy]phenyl}-1H-pyrazol-5-yl)carbonyl]amino}methyl)phenyl]oxy}propanoic acid;    2-methyl-2-{[2-methyl-4-({[(1-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1H-pyrazol-3-yl)carbonyl]amino}methyl)phenyl]oxy}propanoic acid;    2-methyl-2-[(2-methyl-4-{[({1-methyl-5-[4-(2-propen-1-yloxy)phenyl]-1H-pyrazol-3-yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid;    2-({4-[({[3-[4-(1,1-dimethylethyl)phenyl]-1-(2-propen-1-yl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}oxy)-2-methylpropanoic acid;    2-({4-[({[3-[4-(1-dimethylethyl)phenyl]-1-(phenylmethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid; and    2-({4-[({[5-[4-(1,1-dimethylethyl)phenyl]-1-(2-propen-1-yl)-1H-pyrazol-3-yl]carbonyl}amino)methyl]-2-methylphenyl}oxy)-2-methylpropanoic acid.    
   
   
       17 . The compound 2-[(4-{[({5-[4-(1,1-dimethylethyl)phenyl]-1-methyl-1H-pyrazol-3-yl}carbonyl)amino]methyl}-2-methylphenyl)oxy]-2-methylpropanoic acid.  
   
   
       18 . A compound of formula (Ia) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof:  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are independently H or C 1-3  alkyl;  
       R 3  and R 4  are independently H, C 1-6  alkyl, —OC 1-6  alkyl, halogen, OH, C 2-6  alkenyl, or CF 3 ;  
       R 5  is H, C 1-6  alkyl or CF 3 ; and  
       R 7  is C 1-6  alkyl optionally substituted by one or more halogens, halogen, or OC 1-6  alkyl.  
     
   
   
       19 - 21 . (canceled)  
   
   
       22 . A pharmaceutical composition comprising a compound according to  claim 1 .  
   
   
       23 . A pharmaceutical composition according to  claim 22  further comprising a pharmaceutically acceptable carrier.  
   
   
       24 - 25 . (canceled)  
   
   
       26 . A method of treating a hPPAR mediated disease or condition in a patient comprising the administration of a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       27 . A method according to  claim 26  wherein the hPPAR mediated disease or condition is one or more of dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa.